Selection against Pathogenic mtDNA Mutations in a Stem Cell Population Leads to the Loss of the 3243A→G Mutation in Blood

Abstract

The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.

Multisystem manifestations of mitochondrial disorders

“…Recent work on the most common mtDNA point mutation, the A3243G transition, has shed some light on these issues. The proportion of this mutation was shown to exponentially decrease in blood with age, a fact consistent with the existence of a selective process acting at the stem cell level, and explaining why the load of mutant mtDNA in blood is almost invariably lower than in nondividing tissues such as skeletal muscle [88]. It is worth mentioning, however, that although this work offers an unambiguous insight into the mechanisms underlying the loss of pathogenic mutations in a single tissue, it does not elucidate the biological grounds for the erratic phenotypic expression of this mutation.…”

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis

“…The observed level of accumulation of variants present in blood should not be seen as a baseline level, caused by an absence of purifying selection. As a matter of fact, the low number of variants detected in blood samples could be due to selection that acts during life thanks to the rapid turnover of this cell type as already reported in previously published works (Larsson et al, 1990;Ciafaloni et al, 1991;Rajasimha et al, 2008;Pallotti et al, 2014;Kauppila et al, 2016). Interestingly, between PBs, the intra-individual approach indicated unequal accumulation as one thousand times more likely (BF = 9.2e −04 ), but when looking across individuals the result was inverted, and equal accumulation was five times more likely (BF = 5.03).…”

Mitochondrial DNA transcription regulation and nucleoid organization

“…Preferential selection of a particular haplotype also occurs in some tissues of patients harboring pathogenic mtDNA mutations. For instance, mtDNA harboring the A3243G mutation in patients with MELAS tend to be decreased in blood favoring selection of wild-type molecules (Rajasimha et al 2008). Genes encoded by the nucleus have been suggested to be involved in this selective mechanism of mtDNA segregation (Battersby et al 2003).…”